Post-traumatic stress disorder (PTSD) is severe psychiatric disorder that is common amongst veterans, and often highly chronic. PTSD carries frequent comorbidities, causes significant functional impairment and poses staggering personal, societal and financial burdens. Treatment outcomes for PTSD, in particular in veteran populations, are generally poor. No consistently effective alternatives to the main line of psychotherapeutic interventions, which we are already studying the neural correlates of in an ongoing study, have been identified. Thus, there is a pressing clinical need for development of novel treatment interventions. The difficulties associated with treatment of PTSD are further compounded by comorbidity with mild traumatic brain injury (mTBI), which is the signature injury of the conflicts in Afghanistan and Iraq, as well as chronic pain. Considering these comorbidities is important, as studies have shown that the frequencies with which PTSD, TBI and chronic pain co-exist is considerably higher than the frequencies with which they exist in isolation in veterans. It is widely believed that these conditions only serve to further complicate treatment. Neuroscience studies from my lab and others' have found that deficits in the use of executive control processes for emotion- and self-regulation are central to PTSD, along with excessive negative emotional reactivity. We have observed similar neural deficits in patients with chronic pain in isolation. Likewise, data in mTBI also implicates executive functioning and self-regulation. These findings suggest that improvements in executive control and negative emotional reactivity may ameliorate core deficits in PTSD, and its major co- morbidities, mTBI and chronic pain. Emerging research suggests that the neural circuitry that supports executive functions remains plastic and that its activity can be boosted with targeted neuroplasticity-based neurobehavioral interventions, and likewise that negative emotional reactivity can be diminished with training. We recently piloted a neurobehavioral intervention, developed in collaboration with industry partners, aimed at increasing activity in an executive control brain network and diminishing negative emotional reactivity through training with tailored, adaptive and challenging computer-based games. The results of this pilot suggest that this neuroplasticity-based neurobehavioral intervention may be a promising novel treatment intervention for patients with PTSD as well as comorbid mTBI and chronic pain - thus translating cutting-edge neuroscience knowledge about PTSD into a targeted treatment. The internet-delivered training games used in our proposal are very engaging, provide an excellent entry point for treatment, and allow for easy and cost-effective dissemination amongst the many veterans already comfortable with internet- and computer-based games. Wewill recruit 30 veterans with PTSD. At baseline, patients' symptoms will be (1) assessed by a trained clinician using the SCID, PTSD CAPS interview and self-report measures of TBI and chronic pain. They will then (2) complete self-report measurements of their emotion-regulatory abilities, and (3) undergo baseline behavioral and EEG assessments using an emotion regulation task that we have recently found to be abnormal in anxiety disorder patients, including PTSD, as well as other tasks tapping into a variety of executive and emotional functions. Participants will then (4) be randomly assigned to one of two groups (intervention or control games, Ns = 15, respectively). Intervention group participants will complete a 60-day neuroplasticity- based neurobehavioral intervention while control group participants will complete 60-days of games designed to be engaging but which provide no emotion-regulatory benefits. The training will be delivered through the internet via a custom-built website utilizing our existing infrastructure. Assessments and scans identical to those at baseline will be administered post-training, with final clinical follow-up 3 months later. PUBLIC HEALTH RELEVANCE: PTSD is severe psychiatric disorder that is common amongst veterans, often highly chronic, carries frequent comorbidities, causes significant functional impairment and poses staggering personal, societal and financial burdens. Treatment outcomes for veterans with PTSD are generally poor. No consistently effective alternatives to the main line of psychotherapeutic intervention have been identified. Thus, there is a pressing clinical need for development of new treatments. The neuroplasticity-based neurobehavioral intervention that we propose to test in this pilot project may be a promising novel treatment for patients with PTSD - thus translating cutting-edge neuroscience knowledge about deficits in emotion- and self-regulation in PTSD into a targeted treatment boosting these functions. Moreover, the internet-delivered training games used in this program are very engaging, provide an excellent entry point for treatment, and allow for easy and cost-effective dissemination amongst the many veterans already comfortable with internet- and computer-based games.